This year, we published the following accomplishments. (1) We completed four structure-function studies of DNA synthesis by DNA polymerase lambda, an enzyme that participates in repairing DNA lesions resulting from exposure to environmental stress, including radiation. This includes a study of inhibition of Pol lambda by anticancer nucleotide analogs, and the identification of a polymorphic variant of Pol lambda that decreased genome stability and may be associated with increased cancer susceptibility. (2) We published a comprehensive review of DNA replication infidelity in a symposium volume celebrating Darwins birth and publication of the Origin of Species. (3) We published two articles demonstrating that the major replicative DNA polymerases incorporate ribonucleotides during replication in vitro, that one of these (Pol epsilon) incorporates ribonucleotides during replication in yeast, that these ribonucleotides are normally removed by a RNase H2-dependent repair process, and that failure to repair these ribonucleotides results in genome instability via DNA strand misalignments. (4) We contributed one set of experiments to an article from the Elledge group that discovered and characterized a nuclease involved in the repair of interstrand crosslinks. (5) We completed two studies of DNA polymerase nu, a recently discovered human polymerase of unknown function. In one study, we collaborated with the Petrovich group to re-fold Pol nu from inclusion bodies, a novel approach that should facilitate future studies of this enzyme and may be useful for other proteins that are problematic to express in soluble form. In the other study, we collaborated with the Wood group to characterize mutant derivatives of Pol nu, as one step to eventually understand its function and possible contribution to genome stability